Mukaiyama conditions

Under classical Mukaiyama conditions, silyl enol ether 2-372 and the Michael acceptors 2-373 and 2-374 underwent a twofold 1,4-addition to form an enolate in which an ideal set-up exists for an intramolecular aldol reaction. This led to 2-375 with the desired structural core of 2-376 in an overall yield of 42%. 

The intramolecular nitrile oxide-alkene cycloaddition sequence has been used for the assembly of a great variety of natural products. A target that has received special attention is that of taxol (156), undoubtedly due to its unique structural features, its potent anticancer activity, and its hmited availability from natural sources (318,319). In 1984 Kozikowski et al. found that the treatment of nitro dienone 158 (obtained from the p-benzoquinone derivative 157) with p-chlorophe-nyl isocyanate under Mukaiyama conditions afforded the unexpected eight-mem-bered ring 159, which is related to ring B of taxol (156) (Scheme 6.79). 

Aldehyde 14 is reacted with the enolate under Mukaiyama conditions. 

The possibility of asymmetric induction under the fluorous biphase conditions was first speculated upon by Horvath and Rabai [10], and this year has seen the first report of asymmetric catalysis in a fluorous biphase [69]. Two, C2 symmetric salen ligands (29a, b) with four C8Fi7 ponytails have been prepared (Scheme 5) and their Mn(II) complexes evaluated as chiral catalysts for the aerobic oxidation of alkenes under FBS-modified Mukaiyama conditions. Both complexes are active catalysts (isolated yields of epoxides up to 85%) under unusually low catalyst loadings (1.5% cf. the usual 12%). Although catalyst recovery and re-use was demonstrated, low enantioselectivities were observed in most cases. 

Admixing 79 with 75 under Mukaiyama conditions resulted in conversion to disaccharide 80, which proved to be the oidy isomer produced. Once the final methoxyl group was installed as in 81, the OTBS substituent was replaced by OPMB to skirt potential problems with later desilylation that was revealed during the course of ensuing probe experiments. 

Solid-supported nitrile oxides have the main advantage over those prepared in solution that formation of dimers is avoided. Thus, a 96-member library of 3-hydroxymethyl isoxazoles (265) [298] has been prepared from nitroethanol on a modified tetrahydropyranyl linker (263) as nitrile oxide precursor. The cycloaddition step was then performed by generating the nitrile oxide under the Mukaiyama conditions in the presence of alkynes (Scheme 59). As expected, the presence of dimer furoxane was never detected. 

In general, competing 1,2-addition is less of a problem under the Mukaiyama conditions than with corresponding lithium enolates (2). This allows for good yields of conjugate addition products with substrates that give large proportions of 1,2-adducts with enolates. 

The nitrile oxide cycloaddition has been performed on 83 under Mukaiyama conditions giving the isoxazoline 84 in about 50% yields with high stereocontrol of the annulation reaction. 

Mukaiyama conditions were used intramolecularly for the successful closure of an 11-membered ring in Smith s synthesis of normethyljatrophone. 64 Conversion of the alkynyl conjugated ketone in 251 to the silyl-enol ether was followed by reaction with TiCU, leading to reaction with the dioxolane moiety and ring closure (sec. 7.3.B.1 for formation of dioxolanes) to give 252 in 47% yield.l " ... 

Some new square-planar cobalt(III) complexes have been prepared by the reaction of Co(C104)2 6H20 with o-phenylenebis(oxamate) derivatives 23 under aerobic conditions. These complexes have been shown to act as catalysts for the high-yield epoxidation of unfunctionalized tri- and di-substituted olefins (c.g., 24 —> 25) under Mukaiyama conditions. Low yields are obtained with terminal olefins <97TL2377>. 

Naphthyldioxolane derivatives (12) undergo a stereoselective isomerisation to the angular naphtho[l,2-c]pyran under Mukaiyama conditions. The stereochemistry at the 4- and 5- positions of the dioxolane unit controls that at C-3 and C-4 of the isochroman product (94JCS(P1)865). 

While the normal Knorr conditions involve initial N—C bond formation, the overall reaction can also be accomplished under conditions which begin with C—C bond formation. Mukaiyama conditions have been used to condense the dimethyl ketal of acetamidoacetone with silyl enol ethers. The resulting adducts can be cyclized to pyrroles (Scheme 47) <888381 >. 

Solid-phase synthesis of 3-hydroxymethyl isoxazoles 17 was accomplished in acceptable yields and purity through 1,3-DC of different alkynes 15 to resin bound nitrile oxides, generated from nitro compounds 14 under Mukaiyama conditions. This method is robust enough to be carried out by an automated synthesiser <01TL4951>. 

Hudlicky and McKibben reported the cycloaddition of l-chloro-5,6-cis-isopropyhdenedioxycyclohexa-1,3-diene 32 with the nitrile oxide generated from nitroethane 13b under Mukaiyama conditions (Scheme 10) [102]. The bicycUc product 33 formed stereoselectively and regioselectively in 73% yield was projected to be a potential precursor to antibiotics and natural products. 

Isoxazole-isoxazoline polyheterocyclic systems have been synthesized for applications as ionophores using resin boimd alkenes/alkynes as dipo-larophiles. For instance, the isoxazole possessing an alkene moiety 41 was reacted with a nitrile oxide, generated from nitroalkane 13d imder Mukaiyama conditions, to afford isoxazoline 42 in high yield (Scheme 12) [ 104]. 

Silyl enol ethers react with imines under Mukaiyama conditions to give amino-esters. Reaction of 4.24 with imine 4.25, for example, gave a mixture of diastereo-meric methyl 3-(N-phenylamino)-2,3-diphenylpropanoates, 4.26 and 4.27 in a... 

On the other hand, compound 245 was submitted to m-CPBA oxidation and the resulting N-oxide intermediate underwent a Cope reaction in acidic conditions to give N-hydroxypyrrolidine 246 in 77% yield (Scheme 41). The final steps of the synthesis were devoted to the construction of the intramolecular nitrone connection. For this purpose, appHcation of the Mukaiyama conditions generated in a regioselective fashion the nitrone intermediate, which collapsed via an intramolecular 1,3-dipolar cycloaddition to the required strained adduct. Final silyl deprotection furnished virosaine A (38) in 81% yield. 

A tetrahydropyranyl linker is an acid-sensitive linker for alcohols. Nitrile oxides were generated in situ from tetrahydropyranyl-linked nitro alkanes and phenyl isocyanate under Mukaiyama conditions, and reactions with various alkynes gave resin-bound isoxazoles (Scheme 11.39). Cleavage with diluted trifluoroacetic acid gave isoxazoles as primary alcohols in a traceless manner. A library of 3-hydroxymethyl-4,5-disubstituted isoxazoles was prepared in a parallel and automated fashion by a 96-well plate synthesizer with an average yield of 60%. 

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